The existence of the histamine H3 receptor has been known for several years and the receptor is of current interest for the development of new medicaments. Recently, the human histamine H3 receptor has been cloned. The histamine H3 receptor is a presynaptic autoreceptor located both in the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor shows intrinsic, constitutive activity, in vitro as well as in vivo (i.e., it is active in the absence of an agonist). Compounds acting as inverse agonists can inhibit this activity. The histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists could be important mediators of neuronal activity. Accordingly, the histamine H3 receptor is an important target for new therapeutics.
In view of the art's interest in histamine H3 receptor agonists, inverse agonists and antagonists, novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art. Several publications disclose the preparation and use of histamine H3 agonists and antagonists. While earlier H3 ligands were more or less close analogues of histamine, newer imidazole-free ligands of the histamine H3 receptor have been described (see, e.g., Linney et al. in J. Med. Chem. 2000, 43, 2362-2370; U.S. Pat. No. 6,316,475, WO 01/66534, WO 01/74810, see also review by Celanire et al. in Drug Discov. Today 10:1613-1627).
WO 00/66578 claims certain 3- or 4-(imidazol-2-yl)pyridines being substituted in the 4 position of the imidazole ring. It is mentioned that mammals having a disease or condition mediated by NPY can be treated with such a compound.
Our earlier application, WO 2003/066604 (our internal ref.: 6447), claims certain piperazines being substituted in the 1 and 4 positions.
Our earlier application, WO 2005/009976 A1 (our internal ref.: 6739), claims certain 3-(4-isopropylpiperazin-1-yl)-6-phenylpyridazines being substituted in the para position of the phenyl ring. In the specification, no pharmacological data are given for the compounds prepared.
WO 2005/028438 claims certain piperidines being substituted in the 1 and 4 position.